Category Archives: inflammatory bowel disease

NSAIDs and IBD

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While data has shown that nonsteroidal antiinflammatory drugs (NSAIDs) may worsen established IBD, whether these medications may serve as a trigger for IBD is less clear. One recent study indicates that NSAIDs may raise the risk of developing IBD (Ann Intern Med 2012; 156: 350-9).

This study examined the risk by using data from the Nurses Health Study which included 76,795 women.  Aspirin and NSAID use were self-reported.

Results:

  • “123 incident cases of CD and 117 cases of UC occurred over 18 years and 1,295,317 person-years of follow-up”
  • Frequent NSAIDs users (at least 15 days per month) had “increased risk for both CD (absolute difference in age-adjusted incidence, 6 cases per 100,000 person-years [95% CI, 0 to 13]; multivariate hazard ratio, 1.59 [CI, 0.99 to 2.56])”
  • And “UC (absolute difference, 7 cases per 100,000 person-years [CI, 1 to 12]; multivariate hazard ratio, 1.87 [CI, 1.16 to 2.99])”
  • There was no association with acetaminophen or aspirin within the same cohort.  This lessens the possibility of a false association; if subjects were treating GI symptoms, it is likely that an association would have been seen with all analgesics

The authors conclude that any absolute risk is low and therefore more important in understanding mechanism rather than in altering clinical use of these medications.

Link to abstract: Aspirin, nonsteroidal anti-inflammatory drug use, and risk for Crohn …

Additional NSAID references:

  • Gastroenterol 1966; 51: 430.  Sentinel article describing NSAID GI risk.
  • Gastroenterol 2008; 134: 1224.  Use of NSAIDs and risk prevention.
  • Clin Gastro & Hep 2007; 5: 1040. Long term effects of NSAIDs similar to COX-2 selective agents on small bowel mucosal damage (62% had abnormalities vs 50% of COX-2)
  • Clin Gastro & Hep 2006; 4: 1082 & 1090. Consensus on gastroprotection with NSAIDs.
  • Clin Gastro & Hep 2006; 4: 196.  NSAIDs worsen IBD.
  • Clin Gastro & Hep 2003; 1: 160.  Ileitis due to NSAIDs.

Adding Methotrexate to anti-TNF therapy

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While new therapies are emerging for inflammatory bowel disease as noted in recent blog entries on Vedolizumab and Tofacitinib, many patients have refractory disease and require management with available treatments.  One strategy in this situation has been to add methotrexate (Inflamm Bowel Dis 2012; 18: 1488-92).

This case series from the Mayo clinic reported their experience with 14 pediatric Crohn’s patients (10 males) who had methotrexate added to anti-TNF therapy.

Clinical remission was achieved in 50% (PCDAI <15) within 6 weeks with methotrexate (dose: 15 mg/meter squared –average dose 17.5mg SC weekly).  All patients received folate supplementation (1 mg daily). In this study, the average duration of methotrexate use was only 8.2 months & average followup was only 10 months.

Discussion notes that prior to methotrexate all patients had active disease despite anti-TNF therapy & most had received thiopurines. Most patients tolerated methotrexate. Four patients had Clostridium difficile infection; two cases were de novo.  Even after treatment of the infection, patients with Clostridium difficile were refractory to methotrexate treatment.

Of the initial 14 patients, two patients had severe nausea; this resulted in medication discontinuation in one patient and dose reduction in another patient.  No liver or kidney toxicity was identified.

Patients who did not respond to methotrexate, subsequent care including the following: three had surgery, one received tacrolimus/corticosteroids, one received natalizumab, one received certolizumab, and one received adalimumab/corticosteroids (while awaiting screening for certolizumab).

A prospective study of methotrexate is needed to confirm the its effectiveness in refractory Crohn’s and to determine long-term safety and efficacy.

Patient information on methotrexate (from my office website):  Methotrexate

Related blog entries:

Drug levels for inflammatory bowel disease

Methotrexate and liver toxicity

Additional methotrexate references:

-IBD 2011; 17: 2521. Methotrexate therapy: ~25% remission at 1yr, 16% at 2yrs.. n=93.
-JPGN 2011;53: 389. n=64. Supports use of zofran for 1st few months to prevent nausea.
-JPGN 2010; 51: 714. Use of MTX after thiopurines. n=27. 48% in remission at 6 months.
-JPGN 2009; 48: 526. Use in pediatric CD, n=25. 64% response

Adalimumab for children with Crohn’s disease

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While adalimumab has been used in children with refractory Crohn’s disease, there has not been a lot of available data.  However, this situation has improved with the publication of the “IMAgINE 1” study (Hyams JS et al, Gastroenterology 2012; 143: 365-74).

This study enrolled 192 pediatric (6-17 yr-old) patients with moderate to severe Crohn’s disease; patients had PCDAI >30 and had failed conventional therapy with the exception of infliximab.  Approximately 45% in both groups had received prior treatment with infliximab.  The study started as an open-label induction followed by double-blind randomization into either a high-dose or low-dose maintenance phase.

Dosing:  For open label, patients >40 kg received 160 mg at week 0 and 80 mg at week 2.; patients <40 kg, received 80 mg at week 0 and 40 mg at week 2.

For maintenance, high dose was considered 40 mg every other week (eow) if >40 kg, and 20 mg eow if <40 kg.  Low dose was 20 mg and 10 mg respectively based on weight.

Results: 152 of 188 patients completed 26 week study period; 4 patients did not complete induction period.  At week 26, 63 patients (33.5%) were in clinical remission.  The high-dose remission response was 38.7% which was not statistically different from the 28.4% response in the low-dose group.

At week 52, there was a statistically improved response rate in the high-dose group 41.9% compared with low-dose group 28.4%; at the week 52 point, the remission rates were 33.3% compared with 23.2% respectively (p=0.1).  Among patients who were at least 13, it is noted that the overall CDAI clinical remission rate was 51% (week 26) and 36% (week 52) which are comparable to adult data from CHARM study.

Based on previous infliximab: Patients who had prior infliximab did not respond as favorably as infliximab-naive patients.  In the high dose group, the clinical remission at week 26 was 56.9% for infliximab-naive group compared to 16.7% for infliximab-experienced.  Similarly, the infliximab-naive response was higher, 68.6% compared with 47.6% for the infliximab-experienced.

Safety: “No new safety signals were detected.” Yet, 101 of 192 patients had adverse events during open label period, including 2 serious infections (which resolved & patients completed study).  Eight serious infections were noted during double-blind period.  Other safety problems included hepatic-related events in 9 of 188 patients, injection site reactions in 19 patients, hematologic adverse events in 8 patients, and 8 allergic reactions.  There were no reports of malignancy, congestive heart failure, lupus-like syndrome or demyelinating disease.

In both the high-dose and low-dose group, switching to weekly therapy instead of eow was allowed and commonly occurred: 48/95 in low-dose & 35/93 in high-dose.

Reasons for discontinuation: In both groups, drug discontinuation was frequent.  In the low-dose group, 37 patients stopped therapy.  In 18, this was due to lack of efficacy.  The other reasons included adverse effects in 10, protocol violation in 4, withdrew consent in 4, and lost to followup in 1.  In the high-dose group, 27  stopped therapy.  In 11, this was due to lack of efficacy; 12 had adverse effects, 2 withdrew consent, and 1 had protocol violation.

Another recent article (Inflamm Bowel Dis 2012; 18: 685-90) indicates that the annual risk of loss of response to adalimumab was 18% per year of followup.  This study involved 380 CD patients with an average age of 38 years.  This study also showed that there was a significant difference between patients naive to anti-TNF therapy and those who had prior anti-TNF therapy:  8% loss of response per year of followup compared with 22% respectively.

Related blog entries:

TNF-α antagonists and infections

CHOOSE TNF TRIAL

Disease modifying treatment in IBD

Only one chance to make first impression

TNF antagonists and UC

Adalimumab references:

  • -Gut 2011:  Gut doi:10.1136/gut.2010.221127. Use in induction of remission in UC. Reinisch W, et al. Adalimumab for induction of clinical remission in … – Gut – BMJ
  • -Aliment Pharmacol Ther 2010; 32: 1228-39. CHOICE trial. adalimumab effective in pts failing prior IFX.
  • -Gastroenterol 2009; 137: 1628. n=168.  71% & 67% of pts responded by weeks 4 & 12.  61% demonstrated sustained benefit. (in IFX failure pts). Of 156 pts, 65% needed to step up to 40mg weekly and 60 eventually stopped adalimumab due to loss of response.  Lower trough levels associated with loss of effectiveness & often with antibodies to adalimumab (present in 9.2% of pts).
  • -IBD 2011; 17: 2512.  n=50.  62% of pts develop skin reactions: eczema, acne-like dermatitis, psoriasis-like (6 of 50).  Adalimumab d/c’d in 22%.  Message -see dermatologist
  • -Lofberg et al. Am J Gastro 2008; 103: S418 (abstract 1069) Care study. -n=945. Humira at week 20 -remissions in 52% of pts naive to biologics, in 46% who prev responded to IFX & became intolerant, in 40% who prev responded to IFX and lost response, and 36% of pts with primary non-response to IFX.
  • -IBD 2008; 14: S1 Abrstarct 0002. Humira in TNF-naive patients with Crohn’s disease. Decreases hospitalizations. (12 month: 12.7% vs 20.3% in placebo group) Adult dosing: Induction 160mg, then 80mg in 2 weeks, then 40mg every 2 weeks.
  • -IBD 2008; 14: 1683. Response to adalimumab in 10 children.
  • -Gastro 2008; 135: 1493. n=778. mod-to severe Crohn had less hospitalizations (decreased ~60%) and surgery if Rx’d w Humira. 40mg eo week or qweek post 80/40 induction
  • -NEJM 2008; 359: 810. Use in pediatric JRA -helpful.
  • -JPGN 2008; 47: 19. n=15 pediatric patients. Complete or partial response in 64%.
  • -Gastro 2007; 132: 52. CHARM Trial. n=778. 40mg weekly c 47% response at week 26 (17% placebo) & 41% @ week 52 (12% placebo); works nearly as well in pts c prev inliximab as naive pts. Rapid onset ~c/in 2 weeks
  • -Clin Gastro & Hep 2006; 4: 1199-1213. Excellent review. Suggested dosing: 20mg every other week if 20-25kg, 25mg every other week if 25-30kg, 30mg every other week if 30-40kg, 35mg every other week if 40-55kg,  40mg every other week if >55kg, and increase to weekly dosing if needed
  • -JPGN 2008; 46: 1208, 226. pediatric case report and review of CHARM
  • -Gastro 2006; 130: 323-333. CLASSIC-I Trial, n=299. 36% 4-week response to 160mg/80mg week 0/subsequent week 2 (vs. 12% of placebo) All pts naive to anti-TNF Rx.

Adalimumab Injection Pain

  • –Suggestions from GI bulletin board. 1)you let the Humira Pen sit out for about 30 minutes prior to administering the medication, so that it appears clear and not foggy, that it greatly reduces pain at the site. 2) the pain disappeared after adding bicarbonate to the Humira. By trial and error, our nurse found that 0.15cc of bicarbonate is the minimum amount that yields a good effect.
  • -Lidocaine with adalimumab. Abstract reference: AF Ayala, Rosanne S.Groh, Brandt P.Robbins, Lisa M.Scalzi, Lizabeth Bingham, C. April TI The addition of injectable lidocaine to adalimumab results in decreased injection site pain and increased acceptance of therapy. 72nd Annual Scientific Meeting of the American-College-of-Rheumatology/43rd Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals. CY OCT 24-29, 2008 CL San Francisco, CA. They used 0.2 ml 1% lidocaine into prefilled adalimumab syringe. We’ve tried this with a few patients and it seems to work well.
  • -Pt developed a “shot blocker” that is a bristle brush with a central hole for the syringe. The brush diffuses the pain from the Humira injection. Click the link below for a youtube video he created.
  • -http://www.youtube.com/watch?v=nfL95YRlTjY

Vedolizumab -another new IBD treatment

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Occasionally a parent will express concern that their child may run out of effective treatments for inflammatory bowel.  At this time, there are a limited number of effective therapies. If a patient develops reactions or antibodies to medications and/or does not have a clinical response, then the options become quite limited.

Against this backdrop, it is encouraging that new medical treatments are being tested, including Vedolizumab (Inflamm Bowel Dis 2012; 18: 1470-79).

The cited study reports the experience of using Vedolizumab in a randomized controlled phase 2 dose-ranging study in 46 patients (9 placebo, 37 vedolizumab).

Vedolizumab is “a gut-selective monoclonal antibody that antagonizes α4β7 integrin on select subsets of leukocytes binding to MAdCAM-1 on gut vascular endothelium.”  Many have considered vedolizumab to be similar to natalizumab, except it is considered  gut-specific and therefore should not increase the risk of progressive multifocal leukoencephalopathy (PML).  By altering the immune surveillance/lymphocyte tracking of the GI tract and not the brain, theoretically there should not be an increased risk of PML.

Another previous limitation of vedolizumab in small studies was the development of human antihuman antibodies (HAHA) –no joke!  HAHA occurred in up to 44% of patients in previous studies and were associated with reduced efficacy.  As a consequence, a new formulation of vedolizumab has been developed with presumably reduced  immunogenicity.

In the cited study, patients between 18-70 were recruited to receive one to three doses of vedolizumab (2, 6, or 10 mg/kg) or placebo.

Results:

  • Over 50% of vedolizumab-treated patients maintained a clinical response between days 29-253 whereas placebo response ranged between 22-33%.
  • This study was not powered for efficacy; however, the treated patients did have reduced fecal calprotectin.  At baseline, the calprotectin in the treatment groups averaged 405 μg/g and by day 113 had reduced to 54 μg/g.  In contrast, placebo group started with calprotectin of 310 μg/g and dropped to 192 μg/g during same time period.
  • HAHA were detected in 4 (11%)

According to a presentation at DDW (GEMINI I trial), more than 2500 patients have been treated in trials with vedolizumab.  None has developed PML. Encouraging results for efficacy (dosing 300mg IV q4weeks) were also noted; 1 year clinical remission noted in 45% of treated patients compared with 14% of placebo group. Digestive Disease Week 2012 – Vedolizumab Scores on Safety …)

Results of vedolizumab for Crohn’s disease are expected soon as well.

Related blog entries:

Quantifying Risk of PML with Natalizumab

Tofacitinib –a JAK Inhibitor for UC

CHOOSE TNF TRIAL

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While most physicians consider drug efficacy as the most important factor in choosing therapy, this is not always the determinant factor in patient choice.

The “CHOOSE TNF TRIAL” (Inflamm Bowel Dis 2012; 18: 1523-30) was a prospective survey of 100 adult patients with Crohn’s disease who were naive to anti-TNF therapy (infliximab, adalimumab, certolizumab).

Most important to patients:

  • Ease of use 69%
  • Time for therapy 34%
  • Time between applications 31%
  • Evidence for efficacy 19%
  • Fear of syringes 10%

Patient choice: Adalimumab preferred in 36%, certolizumab in 28%, and infliximab in 25%

While patient concerns need to be considered, others have shown that physician opinion is an important factor for patient decisions (J Rhemumatol 2008; 35: 618-24).  The discussion notes that “three anti-TNF drugs used in inflammatory bowel disease treatment have not been compared side-by-side in clinical trials.”  Thus far in pediatrics, infliximab is the only TNF approved for clinical use; as such, the other anti-TNF agents have been used primarily when infliximab loses effectiveness.

One drawback with injectable medications has been reduced adherence; up to 50% of patients fail to maintain regular injection interval; in addition, in patients who have had intravenous infusions (rather than patients who are naive) it is preferred over injections (Jay Popp, medical director of Janssen pharmaceuticals–personal communication).

As such, when patients receive infusions (eg. infliximab), closer followup and better adherence are more likely in comparison to injections.  This certainly improves efficacy.

Related blog entries:

TNF-α antagonists and infections

Disease modifying treatment in IBD

Only one chance to make first impression

How sensitive is Calprotectin?

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A recent article suggests that fecal calprotectin, while good, is not as good as endoscopy at detecting mucosal disease in pediatric Crohn’s disease (Inflamm Bowel Dis 2012; 18: 1493-97).

In this study, 60 consecutive children with new onset untreated Crohn’s disease (diagnosis based on Porto criteria -JPGN 2005; 41: 1-7) were enrolled in ESPGHAN growth study.  The data for this study was collected prospectively (21 investigators from multiple sites).  The calprotectin values were obtained prior to treatment.

Median fecal calprotectin values were 2198 μg/g in patients with isolated small bowel disease; this did not differ significantly from the value of 2400 μg/g in patients with colonic disease (with or without small bowel disease).

Fecal calprotectin was elevated in 95% of patients; this outperformed CRP (86%) and ESR (83%) as a marker for Crohn’s disease.  In the three children with normal calprotectin values, the serum inflammatory markers were normal in all three and two had minimal endoscopic findings.  The histology findings for these three children were not reported.

In my experience, fecal calprotectin has been very useful as a marker for Crohn’s disease and has helped identify some atypical cases by increasing my clinical suspicion.  I have had two patients with high calprotectin values who had normal-appearing mucosa with panendoscopy; they both had small bowel (jejunal) Crohn’s disease; one of these patients did have granulomas identified histologically.

While I realize that no test is perfect, I think additional studies are warranted to determine the actual sensitivity of this test for Crohn’s disease.  The sensitivity of calprotectin may yet be higher than the 95% reported in this study.

Related posts:

Biomarkers identify patients who benefit and how  Multiple additional calprotectin references with this link

Abatacept for IBD?

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Doesn’t work (Gastroenterology 2012; 143: 62-69).  While this study indicates that Abatacept was not effect for either Crohn’s disease (CD) or ulcerative colitis (UC), it was useful nevertheless.

In brief, the study examined four placebo-controlled trials of abatacept for induction and maintenance therapy in both CD and UC.  The induction studies included 451 CD patients and 490 UC patients.  The maintenance studies had 90 CD and 131 UC patients.

Results for induction:

  • CD: Clinical response: 17%, 10%, 15% for abatacept dosing of 30, 10, and 3 mg/kg.  Placebo 14%
  • UC: 21%, 19%, 20%  for abatacept dosing of 30, 10, and 3 mg/kg.  Placebo 29.5%

Results for maintenance:

  • CD: 24% abatacept vs 11% placebo
  • UC: 12.5% vs 14% placebo

The premise of this study was that T-cell activation requires co-stimulatory signaling via T cell CD28 and CD80 or CD86 on the antigen-presenting cell.  Abatacept (CTLA4-Ig) which is effective for psoriasis, rheumatoid arthritis, and juvenile idiopathic arthritis was thought to have potential; it blocks costimulation pathways involved in T-cell activation which was shown to be helpful in animal model of colitis.

So why did it not work?  The editorial in the same volume (pages 13-16) suggests the following possibilities:

  • Abatacept would be more likely to work when naive T cells are actively recruited into inflammation rather than memory T cells which are predominant in IBD
  • CD28-related pathways may not be important in IBD pathogenesis
  • Abatacept may have impeded Treg function in addition to preventing T-cell activation (explained in Fig 1D)
  • Blockade of CD28 pathways could have resulted in unfavorable changes in cytokine profiles from T-cell differentiation (Th1 vs Th2)

The implication of this study is that not all T-cell mediated inflammatory disease respond to the same treatment approaches.  The complexity of intestinal immune responses necessitates ongoing clinical studies to determine which promising therapies will be useful.

Tofacitinib –a JAK Inhibitor for UC

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There are definitely a lot of new therapies on the horizon for inflammatory bowel disease.  One of these agents is likely to be tofacitinib which has shown efficacy for active ulcerative colitis (NEJM 2012; 367: 616-24).

Background: Tofacitinib is a selective oral inhibitor of Janus kinase (JAK) which mediates activity for multiple cytokines, including interleukins 2, 4, 7, 9, 15, and 21.  Blockage of a common signaling molecule by these cytokines “should result in suppression of both T and B cells while maintaining regulatory T-cell function.  It has shown efficacy for organ allograft rejection, rheumatoid arthritis, and psoriasis.”  A previous small study by these investigators did not demonstrate efficacy in Crohn’s disease (Gastroenterology 2011; 140: Suppl: S124 Abstract).

Design: In this study which began as a double-blind, placebo-controlled, phase 2 trial, tofacitinib or placebo was given to 194 adult patients (from 51 centers in 17 countries) with moderate-to-severe active ulcerative colitis. Dosing for tofacitinib included groups receiving 0.5 mg, 3 mg, 10 mg, or 15 mg (all BID).  “The primary outcome was a clinical response at 8 weeks, defined as an absolute decrease from baseline in the score on the Mayo scoring system.”  Most of these patients had failed conventional therapy, including mesalamine, corticosteroids, immunosuppressants, and anti-TNF agents.

Results: At 8 weeks, the primary outcome with the highest doses (10 mg & 15 mg) of tofacitinib had clinical response rates of 61% (p=0.1) and 78% (p<0.001) respectively compared with a 42% placebo response.  Clinical remission (Mayo score ≤ 2) occurred in 48% and 41% respectively (both p<0.001) compared with 10% in placebo group.  Endoscopic remission was noted in 30% and 27% respectively (both p<0.001) compared with 2% of placebo group.

In addition, tofacitinib administration improved CRP values and fecal calprotectin concentrations (Figure 2 of article).

Potential adverse effects included the following

  • neutropenia (ANC 1000-1500) observed in three treated patients
  • two tofacitinib patients (10 mg group) developed abscesses
  • mild increases in LDL and HDL were noted and dose-related (these changes have been seen in rheumatoid arthritis patients as well)

Additional reference:

  • N Engl J Med 2012; 367:495-507 | August 9, 2012.  Tofacitinib for rheumatoid arthritis

What is the GRADE of GM-CSF in IBD?

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I was not familiar with the acronym “GRADE” which refers to an analysis by Cochrane review:

Grading of Recommendations Assessment, Development and Evaluation.

With regard to Sargramostim (GM-CSF), GRADE analysis indicates that GM-CSF does not appear more effective than placebo for Crohn’s disease (Inflamm Bowel Dis 2012; 18: 1333-39).

Three randomized studies were examined with 537 patients.  Clinical remission was achieved in 25.3% of GM-CSF patients compared with 17.5% of placebo-treated patients (p=0.17).  Clinical response (100-point CDAI score drop) was noted in 38.3% of GM-CSF group compared with 24.8% of placebo group (p=0.06).  Adverse effects were not statistically different either.

In my view, there are probably populations of IBD patients who will be benefit from GM-CSF.  The difficulty is identifying which groups.

Additional references:

  • -Gastroenterology 2011; 141: 28, 208.  GM-CSF receptor (CD116) defective expression & function in 85% of IBD pts. n=52.
  • -NEJM 2005; 352: 2193. Leukine decreased Crohn’s dz severity: 48% c decrease in CDAI of >100 (vs 26% placebo). injection & bone pain -common; 3 pts (n=81 in leukine group) c serious rxns- migraine, weakness/lethargy, R-sided weakness (?demyelinating d/o)
  • -Lancet 2002; 360: 1478-1481. use of GM-CSF for Crohn’s.

More on IBD medicine risks

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As noted in a recent post (Assessing and discussing risk of lymphoma in IBD), diagrams can be useful to convey the absolute risks for IBD medicines; this risk is often poorly understood by patients and their families. Two articles add additional insight that may help with counseling. (Thanks to Ben Gold for forwarding these articles.)

  • Am J Gastroenterol 2012; 107: 964-70.
  • Am J Gastroenterol 2012; 107: 1051-63.

The first article reviews the risk of lymphoma with regard to inflammatory bowel disease treatment decisions.  Important points in this article include the following:

1. Relative risks may appear large while absolute risk may be quite low.  The estimate for absolute risk for lymphoma:

  • For azathioprine or 6-mercaptopurine: 1 additional case for every 4357 persons treated
  • For anti-TNF (infliximab, adalimumab, certolizumab): 1 additional case for every 2380 persons treated between ages 20-29.

2. Framing the discussion with regards to risk of continued active disease, continued exposure to steroids, and potential need for surgery can be helpful:

  • “It would take only three patients discontinuing their azathioprine to cause one additional relapse of IBD per year”
  • Seven patients stopping anti-TNF therapy would result in an additional hospitalization each year and 14 patients stopping anti-TNF therapy would result in an additional abdominal surgery each year
  • While the ‘relative risks of lymphoma associated with these medications may sound inappropriately large…A more appropriate comparison is the absolute risk of lymphoma versus the absolute risk of active/untreated disease or corticosteroid therapy.’  An example: if 2000 patients with IBD took one of these medications (eg. anti-TNF agent), probably one patient will develop a lymphoma; however, if none of those patients took an anti-TNF agent, it would result in more than 100 hospitalizations and nearly 60 surgeries.

3. “Patients can also be very sensitive to numerators and pay relatively insufficient attention to denominators.” This has been called “anchoring and adjustment” or “base-rate neglect.”  This issue has to do with “numeracy;” this is defined as the basic math skill needed for health-related activities. To help families, consider the following:

  • avoid labels such as “very low” when describing risk
  • use absolute risk data
  • use similar denominators when comparing risks
  • use visual aids

The second study cited is a pooled analysis of infections, malignancy, and mortality risks associated with infliximab and immunomodulator treatment in adult IBD patients.  This study collected safety data from 10 previous trials.  Five of these trials were randomized, controlled studies.  Table 3 and Table 4 detail extensive safety data for immunomodulators (eg. azathioprine) and for infliximab respectively.

With regard to immunomodulators, the combined studies enrolled 947 on immunomodulators in comparison to 1170 without immunomodulators.  With ulcerative colitis (UC) patients but not with Crohn’s disease (CD), immunomodulator use increased the risk of infections (120/100 patient years versus 92.5 among placebo-treated patients).  CD patients, but not UC patients, had an increased risk of malignancy with immunomodulator use (1.84/100 patient years compared with 0/100 patient years in the control group).  With the exception of the SONIC study, use of immunomodulator was not randomly assigned.  So, some of the increased risk in these patients could be due to having more severe IBD rather than due to the medication.

With regard to infliximab, and in contradiction to the previous article’s estimated risks, infliximab treatment did not appear to affect the incidence of infection, mortality, or malignancy.  This study and several others have not demonstrated an increased risk of malignancy with infliximab. This could be that even with this pooled data it is difficult to detect a rare adverse outcome.  More prospective studies and more long-term followup will be needed to truly determine the risk.

While it is known that these agents may increase the risk of some infections, the limited increase in infections which was detected only with immunomodulator use in UC is likely due to a lowered risk of infection when active inflammatory bowel disease is controlled.  A much bigger risk factor for infection is the use of corticosteroids.  When effective IBD medications are administered, this helps control inflammation and allows tapering of corticosteroids.

Related posts:

TNF-α antagonists and infections

Disease modifying treatment in IBD

Only one chance to make first impression